Members of the tumor necrosis factor (TNF) superfamily play cardinal roles in immunity and] inflammation. TRAIL, the TNF-related apoptosis-inducing ligand, is a member of the TNF family that is capable of inducing apoptosis. Our long-term goal of research is to elucidate the roles of TNF-related apoptosis-inducing proteins in autoimmune diseases. This proposal is based on our recent discovery that TRAIL is a crucial regulator of autoimmune inflammation in the central nervous system (CNS). Chronic blockade of TRAIL in mice exacerbated autoimmune encephalomyelitis and enhanced anti-myelin immune responses. The goal of this proposal is to elucidate the mechanisms of action of TRAIL in animal models of multiple sclerosis. A major challenge to study the roles of TNF/TNF-receptor families of proteins is that they are often expressed by a variety of cell types that perform different functions. In the case of TRAIL and its receptors, they are expressed not only by cells of the immune system that mediate inflammation but also by cells of target organs that succumb to immune destruction. Additionally, TRAIL-related apoptotic proteins often activate opposing signaling pathways in cells, which can either promote (through caspase cascade) or prevent (through NF-_zB or c-Jun) cell death. The roles of TRAIL in different cell types must be established before a comprehensive understanding of its function can be achieved. We hypothesize that, depending on the targets and the signaling pathways that it activates, TRAIL can either promote or prevent autoimmune inflammation. Death signals generated in immune cells and survival signals generated in non-immune cells (such as oligodendrocytes in the CNS) may ameliorate autoimmune disease, whereas death signals generated in oligodendrocytes and survival signals generated in immune cells may promote autoimmune destruction. To test these hypotheses, we will study 1) the roles of TRAIL expressed by immune cells and non-immune cells in experimental autoimmune encephalomyelitis (EAE), 2) the targets of TRAIL action in EAE, 3) the roles of pro- and anti-apoptotic signals generated by TRAIL, and 4) the relationship between TRAIL and FasL in autoimmune inflammation.